This invention relates to pharmaceutical compositions for the nasal administration of benzodiazepine drug compounds. More particularly, this invention relates to pharmaceutical compositions for nasal administration which are in the form of a powder and comprise a benzodiazepine drug compound and chitosan.
The nasal route of drug delivery can afford rapid absorption of drugs into the blood circulation. In some cases absorption of almost the whole dose can be achieved and the pharmacokinetics can be similar to those achieved for intravenous administration. Such rapid and effective drug delivery can be useful in the treatment of crisis situations such as pain (including breakthrough pain, headache), migraine, anxiety, convulsions, impotence and nausea.
A class of compounds of interest for nasal delivery is the benzodiazepines. These lipophilic drugs act on the central nervous system to cause sedation, hypnosis, decreased anxiety, muscle relaxation, anterograde amnesia and anticonvulsant actions and are widely used in medicine. Conditions which they can be used to treat include anxiety, epilepsy, insomnia, alcohol dependence, muscular disorders and mania. These drugs can also be used in premedication procedures and in veterinary practices. Examples of benzodiazepine drugs include but are not limited to alprazolam, chlordiazepoxide, clonazepam, clorazepate, diazepam, estazolam, flurazepam, halazepam, lorazepam, midazolam, nitrazepam, oxazepam, prazepam, quazepam, temazapem, bromazepam, flunitrazepam, triazolam, bentazepam, brotizolam, clotiazepam, delorazepam, ethyl loflazepate, etizolam, fludiazepam, ketozolam, loprazolam, lormetazepam, nordazepam, mexazolam, nimetazepam, pinazepam and tetrazepam. The structures of some of these benzodiazepines can be found in Goodman and Gilman's The Pharmacological Basis of Therapeutics, 9th edition, McGraw Hill (1996), page 363.
The listing or discussion of an apparently prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or is common general knowledge.
The preferred means of delivering drugs for systemic action by the intranasal route is using an aqueous solution formulation. However, lipophilic (non-polar) drugs such as benzodiazepines typically have low aqueous solubility and hence present a significant challenge when designing a nasal formulation.
Drugs may also be delivered intranasally in the form of a powder. However, powder formulations are typically not suitable for intranasal delivery of a lipophilic, poorly-soluble drug since the volume of liquid in the nasal cavity for dissolution is small and the residence time of the formulation in the nasal cavity is low. Consequently, the time available for drug dissolution and therefore absorption, is limited.
The present inventors have surprisingly found that lipophilic, poorly water soluble drugs such as benzodiazepines can be successfully administered intranasally if delivered in the form of a powder containing chitosan. By successfully administered, we mean that therapeutically effective amounts of drug can be absorbed into the systemic circulation.
Chitosan is a bioadhesive cationic biopolymer comprising glucosamine and N-acetyl glucosamine. Chitosan has been shown to improve the systemic bioavailability of certain drug compounds across mucosal surfaces such as the nasal cavity (see Illum, Drug Discovery Today 7, 1184-1189, 2002).
There are number of reports on the use of chitosan to improve the intranasal absorption of polar small molecules such as morphine and peptides such as calcitonin and leuprolide (Ilium, J. Control. Rel., 87, 187-198, 2003) and proteins such as human growth hormone (Cheng et al, Eur. J. Pharm. Sci., 26, 9-15, 2005).
The use of chitosan in powder form to enhance the absorption of lipophilic drugs such as of benzodiazepine drugs has not been reported.